This invention relates to polyazanaphthalen-2-one derivatives (e.g., quinazolin-2-one and pteridin-2-one derivatives) and pharmaceutically acceptable salts thereof, their synthesis, and their use as alpha 1a adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
References are made throughout this application to various publications, the disclosures of which are hereby incorporated by reference in their entireties, in order to more fully describe the state of the art to which this invention pertains.
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha 1, alpha 2, xcex21, and xcex22 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
For a general background on the alpha adrenergic receptors, the reader""s attention is directed to Robert R. Ruffolo, Jr., xcex1-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of alpha 1/alpha 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3xe2x80x2-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity was explored.
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha 1d (formerly known as alpha 1a or 1a/1d), alpha 1b and alpha 1a (formerly known as alpha 1c) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation xe2x80x9calpha 1axe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9calpha 1cxe2x80x9d cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha 1a is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha 1a was renamed alpha 1d. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Michel et al., Naunyn-Schmiedeberg""s Arch. Pharmacol. (1995), 352:1-10.
The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
In benign prostatic hyperplasia, the male hormone 5alpha-dihydrotestosterone has been identified as the principal culprit. The continual production of 5xcex1-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck and Co., Inc.""s product PROSCAR(copyright) (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-xcex1 reductase, which converts testosterone into 5xcex1-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
The development of such agents as PROSCAR(copyright) bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.
In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/00073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alpha 1 subtype was reported. In addition, in WO 92/16213, combinations of 5xcex1-reductase inhibitory compounds and alphal-adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha 1d, alpha 1b, or alpha 1a subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha 1d and alpha 1b receptors in the peripheral vasculature, e.g., hypotension and syncope.
The relatively recent cloning of the human alpha 1a adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha 1a receptor has enabled identification of compounds which specifically interact with the human alpha 1a adrenergic receptor. For further description, see WO 94/08040 and WO 94/10989. As disclosed in the instant patent disclosure, a cloned human alpha 1a adrenergic receptor and a method for identifying compounds which bind the human alpha 1a receptor has made possible the identification of selective human alpha 1a adrenergic receptor antagonists useful for treating BPH.
Several classes of compounds have been disclosed to be selective alpha 1a adrenergic receptor antagonists useful for treating BPH. WO 94/22829 discloses, for example, certain 4-(un)substituted phenyl-1,4-dihydropyridine derivatives which are described as potent, selective alpha 1a antagonists with weak calcium channel antagonistic activity and which are further described to be anticipated as useful for treating BPH. As another example, WO 96/14846, WO 97/17969 and WO 97/42956 each disclose certain dihydropyrimidine derivatives (e.g., certain 1,2,3,6-tetrahydro-2-oxo-pyrimidine derivatives) which are selective antagonists for the human alpha 1a receptor and useful for treatment of BPH, impotency, cardiac arrhythmia, and other diseases where antagonism of the alpha 1a receptor may be useful. As still another example, WO 96/40135 discloses, inter alia, certain phenylpiperidinyl alkyl saccharin derivatives and their use as selective alpha 1a antagonists. Other examples are U.S. Pat. No. 5,661,163 and WO 96/40136, which disclose, inter alia, piperidinyl- and piperazinyl-alkyl-substituted phenyl acetamides. Yet another example is EP 748800, which discloses, inter alia, certain arylpiperazinylpropyl substituted pyrimidinediones useful as alpha 1 adrenoceptor antagonists. Still other alpha 1a selective antagonist compounds are disclosed inWO 98/57632, WO 98/57638, WO 98/57639, WO 98/57640, WO 98/57641 and WO 98/57642.
The instant patent disclosure discloses novel dihydro-polyazanaphthalen-2-one compounds which selectively bind to the human alpha 1a receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha 1a adrenergic receptor.
It is an object of the present invention to identify compounds which bind to the alpha 1a adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha 1a adrenergic receptor. It is another object of the invention to identify alpha 1a adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha 1a adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.
The compounds of the present invention are alpha 1a adrenergic receptor antagonists. Thus, the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha 1a adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.
The present invention provides dihydro-polyazanaphthalen-2-one compounds and pharmaceutically acceptable salts thereof for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). The compounds antagonize the human alpha 1a adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting lower affinity for the alpha 1d and alpha 1b human adrenergic receptors and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
More particularly, the present invention is a compound of formula (I): 
wherein Q is selected from the group consisting of: 
A1, A2, A3 and A4 are each independently selected from Cxe2x80x94X2 and N, provided that no more than two of A1, A2, A3 and A4 are N, and further provided that when two of A1, A2, A3 and A4 are N, each nitrogen atom is bonded to two carbon atoms;
each X1 is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl, or (CH2)0-4ORa;
R1 is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl, phenyl, or substituted phenyl, wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl and (CH2)0-4ORa;
R2 is hydrogen, C1-8 alkyl, or fluorinated C1-C8 alkyl;
R3 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl;
Y is carbon or nitrogen, provided that when Y is nitrogen, R5 is absent;
Z is CH2, CHOH, CHORb, CHF, CHRb, C(Rb)2, CF2, CHCHF2, Cxe2x95x90CF2, or Cxe2x95x90O;
E, G, L and M are each independently selected from hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, (CH2)0-4ORc, (CH2)0-4N(Rc)2, (CH2)0-4CN, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2Rc and (CH2)0-4SO2N(Rc)2;
J is hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, (CH2)1-4ORc, (CH2)1-4N(Rc)2, (CH2)1-4CN, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2Rc, or (CH2)0-4SO2N(Rc)2;
R4 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, thienyl, furanyl, substituted pyridyl, substituted thienyl, or substituted furanyl; wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, ORc, (CH2)0-3CON(Rc)2, (CH2)0-3CO2Rc, methylenedioxy when the phenyl ring is di-substituted and the substituents are on adjacent carbon atoms, C1-C4 alkyl and fluorinated C1-C4 alkyl; and wherein the substituents on the substituted naphthyl, pyridyl, thienyl, or furanyl are independently selected from phenyl, ORc, halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C8 cycloalkyl and fluorinated C3-C8 cycloalkyl;
R5 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, tetrazole, isooxadiazole, phenyl, or substituted phenyl; wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, (CH2)0-3CON(Rc)2, (CH2)0-3CO2Rc, ORc methylenedioxy when the phenyl ring is di-substituted and the substituents are on adjacent carbon atoms, C1-C4 alkyl and fluorinated C1-C4 alkyl;
R6 and R7 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl and fluorinated C3-C8 cycloalkyl;
R8 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, pyridyl N-oxide (Nxe2x86x92O), substituted pyridyl N-oxide, pyrazinyl, substituted pyrazinyl, thienyl, substituted thienyl, thiazolyl, substituted thiazolyl, furanyl, substituted furanyl, quinazolinyl, or substituted quinazolinyl; wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, ORc, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-4 alkyl and fluorinated C1-C4 alkyl; and wherein the substituents on the substituted naphthyl, pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, or quinazolinyl are independently selected from cyano, nitro, N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C8 cycloalkyl and fluorinated C3-C8 cycloalkyl;
R9 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl;
R10 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, tetrazole, isooxadiazole, phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, thienyl, substituted thienyl, furanyl, or substituted furanyl; wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, nitro, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-C4 alkyl and fluorinated C1-C4 alkyl; and wherein the substituents on the substituted naphthyl, pyridyl, thienyl, or furanyl are independently selected from (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl and C3-C8 cycloalkyl;
R13, R14, R15 and R16 are each independently selected from hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, and (CH2)2-4ORc;
R18 and R20 are each independently selected from hydrogen and ORd;
Ra is hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, or C3-C8 cycloalkyl;
Rb is C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, or fluorinated C3-C8 cycloalkyl;
Rc is hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, or fluorinated C3-C8 cycloalkyl;
Rd is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or (CH2)0-4CF3;
m, n, o, and p are each independently integers from 0 to 3;
q1 is an integer from 0 to 5;
t is an integer from 2 to 5;
u and v are each independently integers from 0 to 3; provided that u and v are not both zero; and further provided that when u=0, Z is selected from CH2, CHF, CHRb, C(Rb)2, CF2, CHCHF2 and Cxe2x95x90CF2; and
w is an integer from 0 to 3, provided that when w is 0, R20 is hydrogen;
or a pharmaceutically acceptable salt thereof.
The present invention also includes pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treatment.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
The present invention includes dihydro-polyazanaphthalen-2-one compounds of Formula (I) above. These compounds and their pharmaceutically acceptable salts are useful as alpha 1a antagonists.
In a first embodiment, the present invention is a compound of Formula (I), wherein
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa;
R1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, phenyl, or substituted phenyl, wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl and (CH2)0-4ORa;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
E, G, L and M are each independently selected from hydrogen and C1-C4 alkyl;
J is hydrogen or C1-C4 alkyl;
R4 is phenyl, mono- or di- or tri-substituted phenyl, pyridyl, thienyl, or furanyl;
wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, CO2Rc, ORc, CON(Rc)2, methylenedioxy, C1-C4 alkyl and fluorinated C1-C4 alkyl;
R5 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl, wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, CO2Rc, ORc, CON(Rc)2, methylenedioxy, C1-C4 alkyl and fluorinated C1-C4 alkyl;
one of R6 and R7 is hydrogen, and the other of R6 and R7 is hydrogen or C1-C4 alkyl;
R8 is phenyl, mono- or di- or tri-substituted phenyl, pyridyl, or mono- or di- or tri-substituted pyridyl; wherein the substituents on the phenyl are independently selected from halogen, cyano, ORc, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-4 alkyl and CF3; and wherein the substituents on the substituted pyridyl are independently selected from cyano, nitro, N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl ORc, halogen, C1-C4 alkyl and CF3;
R9 is hydrogen, C1-C4 alkyl, or fluorinated C1-C4 alkyl;
R10 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc and C1-C4 alkyl;
R13, R14, R15 and R16 are each independently selected from hydrogen and C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rb is C1-C4 alkyl or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rd is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
m, n, o, and p are each independently 0 or 1;
q1 is an integer from 0 to 4; and
all other variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
In a second embodiment, the present invention is a compound of Formula (I),
wherein each of A1, A2, A3 and A4 is Cxe2x80x94X2; and
all other variables are as defined in the first embodiment
or a pharmaceutically acceptable salt thereof.
In a third embodiment, the present invention is a compound of Formula (I), wherein Q is 
each of A1, A2, A3 and A4 is Cxe2x80x94X2;
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa;
R1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, phenyl, or substituted phenyl, wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl and (CH2)0-4ORa;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
R4 is phenyl, mono- or di- or tri-substituted phenyl, pyridyl, thienyl, or furanyl;
wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, CO2Rc, ORc, CON(Rc)2, methylenedioxy, C1-C4 alkyl and fluorinated C1-C4 alkyl;
R5 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl, wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, CO2Rc, ORc, CON(Rc)2, methylenedioxy, C1-C4 alkyl and fluorinated C1-C4 alkyl;
one of R6 and R7 is hydrogen, and the other of R6 and R7 is hydrogen or C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rb is C1-C4 alkyl or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
q1 is an integer from 0 to 4; and
all other variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
In a first class of the invention is a compound of Formula (II): 
wherein Z is CH2, CHOH or Cxe2x95x90O;
each X3 is independently hydrogen, CF3, cyano, halogen, or C1-C4 alkyl;
R5 is hydrogen, cyano, or CO2Rc;
q2 is an integer from 0 to 4;
q3 is an integer from 0 to 3; and
all other variables are as defined in the third embodiment;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the first class is a compound of formula (III): 
each X1 is independently hydrogen, fluorine, methyl, ethyl, cyano, CF3, methoxy, ethoxy, or OCF3;
each X3 is independently hydrogen, CF3, cyano, fluorine, methyl, or ethyl;
q1 is an integer from 0 to 2; and
all other variables are as defined in the first class;
or a pharmaceutically acceptable salt thereof.
Exemplifying the invention is a compound selected from the group consisting of:
4-(3,4-difluorophenyl)-3-((4-cyano-4-(2-cyanophenyl)piperidin-1-yl)propylcarbamoyl)-3,4-dihydro-quinazolin-2-one;
4-(3,4-difluorophenyl)-3(-(4-(4-fluorophenyl)piperidin-1-yl)propylcarbamoyl)-3,4-dihydro-quinazolin-2-one;
and pharmaceutically acceptable salts thereof.
In a fourth embodiment, the present invention is a compound of Formula (I), wherein Q is 
each of A1, A2, A3 and A4 is Cxe2x80x94X2;
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa;
R1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, phenyl, or substituted phenyl, wherein the substituents on the substituted phenyl are independently selected from halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl and (CH2)0-4ORa;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
E, G, L and M are each independently selected from hydrogen and C1-C4 alkyl;
J is hydrogen or C1-C4 alkyl;
one of R6 and R7 is hydrogen, and the other of R6 and R7 is hydrogen or C1-C4 alkyl;
R8 is selected from phenyl, mono- or di- or tri-substituted phenyl, pyridyl, or mono- or di- or tri-substituted pyridyl; wherein the substituents on the phenyl are independently selected from halogen, cyano, ORc, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-4 alkyl and wherein the substituents on the substituted pyridyl are independently selected from cyano, N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl and CF3;
R10 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl, wherein the substituents on the phenyl are independently selected from halogen, cyano, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc and C1-C4 alkyl;
R13, R14, R15 and R16 are each independently selected from hydrogen and C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rd is hydrogen, C1-C4 alkyl, or (CH2)0-4CF3;
m, n, o, and p are each independently 0 or 1;
q1 is an integer from 0 to 4; and
all other variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
In a second class of the invention is a compound of Formula (IV): 
wherein T is Cxe2x80x94X3 or N;
each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, C1-4 alkyl, or CF3;
R10 is hydrogen, cyano, or ORc;
R20 is hydrogen or OH;
q2 is an integer from 0 to 4;
q3 is an integer from 0 to 3;
w is 0 or 1, provided that when w is 0, R20 is hydrogen; and
all other variables are as defined in the fourth embodiment;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the second class is a compound of formula (IV), wherein each X1 is fluorine;
each X2 is hydrogen;
R20 is hydrogen;
q1 is an integer from 0 to 3;
w is 1; and
all other variables are as defined in the second class;
or a pharmaceutically acceptable salt thereof.
Also exemplifying the invention is a compound selected from the group consisting of:
trans-4-(3,4-difluorophenyl)-3-((1-(4-(2-cyanophenyl)cyclohexyl)-3-hydroxy-azetidin-3-yl)methylcarbamoyl)-3,4-dihydro-quinazolin-2-one;
trans-4-(3,4-difluorophenyl)-3-((1-(4-(2-cyanophenyl)cyclohexyl)azetidin-3-yl)methylcarbamoyl)-3,4-dihydro-quinazolin-2-one;
trans-4-(3,4-difluorophenyl)-3-((1-(4-(2-pyridyl)cyclohexyl)azetidin-3-yl)methylcarbamoyl)-3,4-dihydro-quinazolin-2(3H)-one;
and pharmaceutically acceptable salts thereof.
In a third class of the invention is a compound of Formula (V): 
wherein
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa; each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, C1-4 alkyl, or CF3;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
R10 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl, wherein the substituents on the phenyl are independently selected from halogen, cyano, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-C4 alkyl and fluorinated C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
t is an integer from 2 to 4; and
q1, q2 and q3 are each independently integers from 0 to 4;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the third class is a compound of formula (V), wherein
each X1 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3;
each X2 is hydrogen;
each X3 is independently hydrogen, halogen, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, CF3, or OCF3;
R2 is hydrogen;
R3 is hydrogen;
R9 is hydrogen;
R10 is hydrogen, cyano, or ORc;
Rc is hydrogen, methyl, or ethyl;
t is 2 or 3;
q1 and q3 are each independently integers from 0 to 3; and
all other variables are as defined in the third class;
or a pharmaceutically acceptable salt thereof.
In a fourth class of the invention is a compound of Formula (VI): 
wherein
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(R(c)2, SO2N(Rc)2, SO2Rc, C1-4 alkyl, or CF3;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
t is an integer from 2 to 4; and
q1, q2 and q3 are each independently integers from 0 to 4;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the fourth class is a compound of formula (VI), wherein
each X1 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3;
each X2 is hydrogen;
each X3 is independently hydrogen, halogen, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, CF3, or OCF3;
R2 is hydrogen;
R3 is hydrogen;
R9 is hydrogen;
Rc is hydrogen, methyl, or ethyl;
t is 2 or 3;
q1 and q3 are each independently integers from 0 to 3; and
all other variables are as defined in the fourth class;
or a pharmaceutically acceptable salt thereof.
In a fifth class of the invention is a compound of Formula (VII): 
wherein
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, C1-4 alkyl, or CF3;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
o and p are each independently 0 or 1;
w is an integer from 0 to 2; and
q1, q2 and q3 are each independently integers from 0 to 4;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the fifth class is a compound of formula (VII), wherein
each X1 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3;
each X2 is hydrogen;
each X3 is independently hydrogen, halogen, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, CF3, or OCF3;
R2 is hydrogen;
R3 is hydrogen;
Rc is hydrogen, methyl, or ethyl;
w is 0 or 1;
q1 and q3 are each independently integers from 0 to 3; and
all other variables are as defined in the fifth class;
or a pharmaceutically acceptable salt thereof.
In a sixth class of the invention is a compound of Formula (VIII): 
wherein
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, C1-4 alkyl, or CF3;
R2 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
R10 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl, wherein the substituents on the phenyl are independently selected from halogen, cyano, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-C4 alkyl and fluorinated C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
o and p are each independently 0 or 1;
w is an integer from 0 to 2;
q1, q2 and q3 are each independently integers from 0 to 4;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the sixth class is a compound of formula (VIII), wherein
each X1 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3;
each X2 is hydrogen;
each X3 is independently hydrogen, halogen, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, CF3, or OCF3;
R2 is hydrogen;
R9 is hydrogen;
R10 is hydrogen, cyano, or ORc;
Rc is hydrogen, methyl, or ethyl;
w is 0 or 1;
q1 and q3 are each independently integers from 0 to 3; and
all other variables are as defined in the sixth class;
or a pharmaceutically acceptable salt thereof.
In a seventh class of the invention is a compound of Formula (IX): 
wherein
each X1 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X2 is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa;
each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, C1-4 alkyl, or CF3;
R2 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
Ra is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
Rc is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3;
o and p are each independently 0 or 1;
w is an integer from 0 to 2; and
q1, q2 and q3 are each independently integers from 0 to 4;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the seventh class is a compound of formula (IX), wherein
each X1 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3;
each X2 is hydrogen;
each X3 is independently hydrogen, halogen, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, CF3, or OCF3;
R2 is hydrogen;
R9 is hydrogen;
Rc is hydrogen, methyl, or ethyl;
w is 0 or 1;
q1 and q3 are each independently integers from 0 to 3; and
all other variables are as defined in the seventh class;
or a pharmaceutically acceptable salt thereof.
The present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. In one embodiment is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. The present invention further includes a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
The present invention further includes a pharmaceutical composition as described in the preceding paragraph further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. In one embodiment, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor), or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. In another embodiment, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. The testosterone 5-alpha reductase inhibitor is suitably finasteride.
The present invention also includes a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. In one embodiment of the method of treating BPH, the compound (or composition) does not cause a fall in blood pressure at dosages effective to alleviate BPH. In another embodiment of the method of treating BPH, the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. A suitable testosterone 5-alpha reductase inhibitor for use in the method is finasteride.
The present invention also includes a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. In one embodiment of the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue, the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to inhibit contraction of prostate tissue. In another embodiment, the compound is administered in combination with a testosterone 5-alpha reductase inhibitor; the testosterone 5-alpha reductase inhibitor is suitably finasteride.
The present invention also includes a method of treating a disease which is susceptible to treatment by antagonism of the alpha 1a receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha 1a receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see Vatz, Headache (1997), 37: 107-108) and cardiac arrhythmia.
The present invention also includes the use of any of the compounds described above in the preparation of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
The present invention further includes the use of any of the alpha 1a antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha 1a antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
As used herein, the term xe2x80x9cC1-C8 alkylxe2x80x9d means linear or branched chain alkyl groups having from 1 to 8 carbon atoms and includes all of the octyl alkyl, heptyl alkyl, hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1-C4 alkylxe2x80x9d means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d means an xe2x80x94O-alkyl group wherein alkyl is C1 to C6 alkyl. xe2x80x9cC1-C4 alkoxyxe2x80x9d has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy.
The term xe2x80x9cC3-C8 cycloalkylxe2x80x9d means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). xe2x80x9cC3-C6 cycloalkylxe2x80x9d refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9cC1-C8 alkyl-C3-C8 cycloalkylxe2x80x9d means a C3-C8 cycloalkyl group as defined above substituted with one or more linear or branched chain alkyl groups having from 1 to 8 carbon atoms.
The term xe2x80x9cC3-C8 cycloalkyl-C1-C8 alkylxe2x80x9d means a C1-C8 alkyl group as defined above substituted with one or more cyclic alkyl groups having from 3 to 8 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d (which may alternatively be referred to as xe2x80x9chaloxe2x80x9d) refers to fluorine, chlorine, bromine and iodine (alternatively, fluoro, chloro, bromo, and iodo).
The term xe2x80x9cfluorinated C1-C8 alkylxe2x80x9d (which may alternatively be preferred to as xe2x80x9cC1-C8 fluoroalkylxe2x80x9d) means a C1 to C8 linear or branched alkyl group as defined above with one or more fluorine substituents. The term xe2x80x9cfluorinated C1-C4 alkylxe2x80x9d has an analogous meaning. Representative examples of suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.), 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl, and perfluorohexyl.
The term xe2x80x9cfluorinated C3-C8 cycloalkylxe2x80x9d (which may alternatively be referred to as xe2x80x9cC3-C8 fluorocycloalkylxe2x80x9d) means a cycloalkyl group as defined above with one or more fluorine substituents. xe2x80x9cFluorinated C3-C6 cycloalkylxe2x80x9d has an analogous meaning. Representative examples of suitable fluorocycloalkyls include all isomers of fluorocyclohexyl (i.e., 1-, 2-, 3-, and 4-fluorocyclohexyl), difluorocyclohexyl (e.g., 2,4-difluorocyclohexyl, 3,4-difluorocyclohexyl, etc.), fluorocyclopentyl, and so forth.
The term xe2x80x9cfluorinated C1-C6 alkoxyxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C6 fluoroalkoxyxe2x80x9d) means a C1-C6 alkoxy group as defined above wherein the alkyl moiety has one or more fluorine substituents. xe2x80x9cFluorinated C1-C4 alkoxyxe2x80x9d has an analogous meaning. Representative examples include the series O(CH2)0-4CF3 (i.e., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.
The term xe2x80x9cheterocyclicxe2x80x9d (which may alternatively be referred to as xe2x80x9cheterocyclexe2x80x9d) refers to a stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated; which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized; and which is optionally substituted with one or more substituent groups including, but not limited to, halo, cyano, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, alkylalkoxy, cycloalkyl, fluorocycloalkyl, amino, aryl (e.g., phenyl), carboxy, carboxylate, sulfonamido, sulfonyl, and the like. Suitable heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term xe2x80x9cthienyl,xe2x80x9d as used herein, refers to the group 
The term xe2x80x9carylxe2x80x9d refers herein to aromatic mono- and poly-carbocyclic ring systems, optionally substituted, including, but not limited to, phenyl, substituted phenyl, naphthyl, and substituted naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic heterocyclic or substituted aromatic heterocyclic ring systems, including, but not limited to, pyridyl, substituted pyridyl, pyridyl N-oxide (N{circle around (7)}O), substituted pyridyl N-oxide, pyrazinyl, substituted pyrazinyl, thienyl, substituted thienyl, thiazolyl, substituted thiazolyl, furanyl, substituted furanyl, quinazolinyl, and substituted quinazolinyl.
The term xe2x80x9csubstitutedxe2x80x9d includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed.
It is understood that the definition of a substituent (e.g., CO2Rc) or variable (e.g., Rc) at a particular location in a molecule is independent of its definitions at other locations in that molecule. Thus, for example, when R4 is mono-substituted phenyl wherein the substituent is CO2Rcxe2x95x90CO2H, and R5 is also mono-substituted phenyl wherein the substituent is CO2Rc, it is understood that the substituent on the phenyl in R5 can be any one of CO2H, CO2Me, CO2Et, CO2Pr, CH2CO2H, CH2CO2Me, CH2CO2Et, CH2CO2Pr, (CH2)2CO2H, etc. As another example, NRcC(xe2x95x90O)Rc represents NHC(xe2x95x90O)H, NHC(xe2x95x90O)Me, NMeC(xe2x95x90O)Me, NMeC(xe2x95x90O)Et, etc.
It is also understood that the definition of a substituent or variable at a particular location in a molecule is independent of the definition of another occurrence of the same substituent or variable at the same location. Thus, C(xe2x95x90O)N(Rc)2 represents groups such as xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NHCH3, xe2x80x94C(xe2x95x90O)NHC2H5, xe2x80x94C(xe2x95x90O)N(CH3)C2H5, etc.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by the methods set forth below and, when viewed in the light of this disclosure, by techniques known in the art. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. Representative embodiments for the variables and substituents set forth in Formula (I) include the following:
A1, A2, A3 and A4 are each independently selected from Cxe2x80x94X2 or N, provided that no more than two of A1, A2, A3 and A4 are nitrogen, and further provided that when two of A1, A2, A3 and A4 are N, each nitrogen atom is bonded to two carbon atoms. In one embodiment, A1 and A4 are nitrogen and A2 and A3 are Cxe2x80x94X2. In another embodiment, A2 and A4 are nitrogen and A1 and A3 are Cxe2x80x94X2. In yet another embodiment, one of A1, A2, A3 and A4 is nitrogen, and the others are Cxe2x80x94X2. In still another embodiment, all of A1, A2, A3 and A4 are Cxe2x80x94X2.
Each X1 is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl, or (CH2)0-4ORa; or is independently hydrogen, halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa; or is independently hydrogen, halogen, cyano, C1-C4 alkyl, (CH2)0-4CF3, or (CH2)0-4CF3; or is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa. In another embodiment, each X1 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3. In another embodiment, each X1 is independently hydrogen, fluorine, cyano, methyl, ethyl, CF3, or OCF3. In still another embodiment, each X1 is fluorine.
Each X2 is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl, or (CH2)0-4ORa; or is independently hydrogen, halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C3-C6 cycloalkyl, or (CH2)0-4ORa; or is independently hydrogen, halogen, cyano, C1-C4 alkyl, (CH2)0-4CF3, or (CH2)0-4CF3; or is independently hydrogen, halogen, cyano, C1-C4 alkyl, CF3, or (CH2)0-4ORa. In another embodiment, each X2 is independently hydrogen, halogen, cyano, methyl, ethyl, CF3, or OCF3. In still another embodiment, each X2 is hydrogen.
One aspect of the embodiment in which all of A1, A2, A3 and A4 are Cxe2x80x94X2 is the dihydroquinazolin-2-one moiety of formula: 
wherein X2 is as defined above; and q2 is an integer from 0 to 4; or from 0 to 3; or from 0 to 2; or is 0 or 1; or is 0; or is 1.
R1 is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl, phenyl, or substituted phenyl; or is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, phenyl, or substituted phenyl; or is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl, phenyl, or mono- or di- or tri-substituted phenyl. In another embodiment, R1 is hydrogen.
In R1, the substituents on the substituted phenyl are independently selected from halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C3-C8 cycloalkyl and (CH2)0-4ORa; or are independently selected from halogen, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, fluorinated C3-C6 cycloalkyl and (CH2)0-4ORa.
R2 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl; or is hydrogen, C1-C4 alkyl, or fluorinated C1-C4 alkyl; or is hydrogen or C1-C4 alkyl. In another embodiment, R2 is hydrogen.
R3 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl; or is hydrogen, C1-C4 alkyl, or fluorinated C1-C4 alkyl; or is hydrogen or C1-C4 alkyl. In another embodiment, R3 is hydrogen.
Y is carbon or nitrogen, provided that when Y is nitrogen, R5 is absent. In one embodiment, Y is carbon.
Z is CH2, CHORb, CHF, CHRb, C(Rb)2, CF2, CHCHF2, Cxe2x95x90CF2, or Cxe2x95x90O. In one embodiment, Z is CH2, CHF, CHRb, C(Rb)2, CF2, CHCHF2, or Cxe2x95x90CF2. In another embodiment, Z is CH2, CHOH, or Cxe2x95x90O, provided that when u is zero, Z is CH2.
E, G, L and M are each independently selected from hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, (CH2)0-4ORc, (CH2)0-4N(Rc)2, (CH2)0-4CN, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2Rc and (CH2)0-4SO2N(Rc)2; or are each independently selected from hydrogen, C1-C4 alkyl and fluorinated C1-C4 alkyl; or are each independently selected from hydrogen, C1-C4 alkyl and (CH2)0-3CF3; or are each independently selected from hydrogen and C1-C4 alkyl. In one embodiment, E, G, L and M are all hydrogen.
J is hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, (CH2)1-4ORc, (CH2)1-4N(Rc)2, (CH2)1-4CN, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2Rc, or (CH2)0-4SO2N(Rc)2; or is hydrogen, C1-C4 alkyl or fluorinated C1-C4 alkyl; or is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3; or is hydrogen or C1-C4 alkyl; or is hydrogen.
R4 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, thienyl, furanyl, substituted pyridyl, substituted thienyl, or substituted furanyl; or is phenyl, mono- or di- or tri-substituted phenyl, pyridyl, thienyl, or furanyl; or is phenyl or mono- or di- or tri-substituted phenyl; or is phenyl or mono-substituted phenyl.
In R4, the substituents on the substituted phenyl are independently selected from halogen, cyano, ORc, (CH2)0-3CON(Rc)2, (CH2)0-3CO2Rc, methylenedioxy when the phenyl ring is di-substituted and the substituents are on adjacent carbon atoms, C1-C4 alkyl and fluorinated C1-C4 alkyl; or are independently selected from halogen, cyano, CO2Rc, ORc, CON(Rc)2, methylenedioxy, C1-C4 alkyl and fluorinated C1-C4 alkyl; or are independently selected from CF3, cyano, halogen (e.g., fluorine), and C1-C4 alkyl.
In R4, the substituents on the substituted naphthyl, pyridyl, thienyl, or furanyl are independently selected from phenyl, ORc, halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C8 cycloalkyl and fluorinated C3-C8 cycloalkyl; or are independently selected from CF3, phenyl, ORc, halogen, and C1-C4 alkyl.
In one embodiment, R4 is represented by the formula: 
wherein each X3 is independently halogen, cyano, ORc, (CH2)0-3CON(Rc)2, (CH2)0-3CO2Rc, C1-C4 alkyl or fluorinated C1-C4 alkyl; and q3 is an integer of from 0 to 5; or from 0 to 4; or from 0 to 3; or from 0 to 2; or is 0 or 1. In other embodiments, each X3 is independently hydrogen, halogen, cyano, ORc, CO2Rc, CON(Rc)2, SO2N(Rc)2, SO2Rc, C1-C4 alkyl, or CF3; or is independently hydrogen, CF3, cyano, halogen, or C1-C4 alkyl; or is independently hydrogen, CF3, cyano, fluorine, methyl, or ethyl; or is independently hydrogen, CF3, cyano, or fluorine.
R5 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, tetrazole, isooxadiazole, phenyl, or substituted phenyl; or is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl; or is hydrogen, cyano, CO2Rc, CON(Rc)2, tetrazole and isooxadiazole; or is hydrogen, cyano, or CO2Rc; or is cyano or CO2Rc. In one embodiment, R5 is cyano or CO2CH3.
In R5, the substituents on the substituted phenyl are independently selected from halogen, cyano, (CH2)0-3CON(Rc)2, (CH2)0-3CO2Rc, methylenedioxy when the phenyl ring is di-substituted and the substituents are on adjacent carbon atoms, C1-C4 alkyl and fluorinated C1-C4 alkyl; or are independently selected from halogen, cyano, CO2Rc, ORc, CON(Rc)2, methylenedioxy, C1-C4 alkyl and fluorinated C1-C4 alkyl.
R6 and R7 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl and fluorinated C3-C8 cycloalkyl; or one of R6 and R7 is hydrogen, and the other of R6 and R7 is hydrogen or C1-C4 alkyl. In another embodiment, R6 and R7 are both hydrogen. In still another embodiment, R6 and R7 together with the carbon atom to which they are attached form methylene (xe2x80x94CH2xe2x80x94) units or alkylidene units of formula (xe2x80x94CRxe2x80x2Hxe2x80x94) wherein Rxe2x80x2 is C1-C4 alkyl or, in cases where there are at least two CR6R7""s (e.g., when w=2), mixtures of the foregoing units.
R8 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, pyridyl N-oxide (N{circle around (7)}O), substituted pyridyl N-oxide, pyrazinyl, substituted pyrazinyl, thienyl, substituted thienyl, thiazolyl, substituted thiazolyl, furanyl, substituted furanyl, quinazolinyl, or substituted quinazolinyl; or is phenyl, mono- or di- or tri-substituted phenyl, pyridyl, or mono- or di- or tri-substituted pyridyl; or is phenyl or mono- or di- or tri-substituted phenyl.
In R8, the substituents on the phenyl are independently selected from halogen, cyano, nitro, ORc, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-4 alkyl and fluorinated C1-C4 alkyl; or are independently selected from halogen, cyano, ORc, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-4 alkyl and CF3; or are independently selected from CF3, cyano, halogen (e.g., fluorine), and C1-C4 alkyl.
In R8, the substituents on the substituted naphthyl, pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, or quinazolinyl are independently selected from cyano, nitro, N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C8 cycloalkyl and fluorinated C3-C8 cycloalkyl; or are independently selected from cyano, nitro, N(Rc)2, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl and CF3.
In one embodiment, R8 is represented by the formula: 
wherein X3 and q3 are as defined above.
R9 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl; or is hydrogen, C1-C4 alkyl, or fluorinated C1-C4 alkyl. In another embodiment, R2 is hydrogen.
R10 is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, tetrazole, isooxadiazole, phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, thienyl, substituted thienyl, furanyl, or substituted furanyl; or is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di- or tri-substituted phenyl; or is hydrogen, cyano, ORc, CO2Rc, CON(Rc)2, phenyl, or mono- or di-substituted phenyl; or is hydrogen, cyano, or ORc.
In R10, the substituents on the substituted phenyl are independently selected from halogen, cyano, nitro, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, C1-C4 alkyl and fluorinated C1-C4 alkyl; or are independently selected from halogen, cyano, ORc, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, N(Rc)2, NRcCORc, NRcCON(Rc)2, NRcSO2Rc, NRcSO2N(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc and C1-C4 alkyl; or are independently selected from halogen, cyano, ORc, (CH2)0-2CO2Rc, (CH2)0-2CON(Rc)2 and C1-C4 alkyl.
In R10, the substituents on the substituted naphthyl, pyridyl, thienyl, or furanyl are independently selected from (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl and C3-C8 cycloalkyl; or are independently selected from CF3, (CH2)0-4CO2Rc, (CH2)0-4CON(Rc)2, (CH2)0-4SO2N(Rc)2, (CH2)0-4SO2Rc, phenyl, ORc, halogen, C1-C4 alkyl and C3-C8 cycloalkyl.
In one embodiment, R10 is represented by the formula: 
wherein X3 and q3 are as defined above.
R13, R14, R15 and R16 are each independently selected from hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, and (CH2)2-4ORc; or are each independently selected from hydrogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, and (CH2)2-4ORb; or are each independently selected from hydrogen, C1-C4 alkyl and fluorinated C1-C4 alkyl; or are each independently selected from hydrogen, C1-C4 alkyl and (CH2)1-4CF3; or are each independently selected from hydrogen and C1-C4 alkyl. In one embodiment, R13, R14, R15 and R16 are all hydrogen.
R18 and R20 are each independently selected from hydrogen and ORd; or are each independently selected from hydrogen, hydroxy, methoxy, ethoxy, and CF3; or are each independently selected from hydrogen and hydroxy (e.g., R18 and R20. are both hydrogen or both hydroxy).
Ra is hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, or C3-C8 cycloalkyl; or is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3; or is hydrogen, methyl, ethyl, or CF3; or is hydrogen, methyl, or ethyl.
Rb is C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, or fluorinated C3-C8 cycloalkyl; or is C1-C4 alkyl or (CH2)0-3CF3; or is methyl, ethyl, or CF3; or is methyl or ethyl.
Rc is hydrogen, C1-C8 alkyl, fluorinated C1-C8 alkyl, C3-C8 cycloalkyl, or fluorinated C3-C8 cycloalkyl; or is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3; or is hydrogen, methyl, ethyl, or CF3; or is hydrogen, methyl, or ethyl.
Rd is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or (CH2)0-4CF3; or is hydrogen, C1-C4 alkyl, or (CH2)0-3CF3; or is hydrogen, methyl, ethyl, or CF3; or is hydrogen, methyl, or ethyl.
m, n, o, and p are each independently integers from 0 to 3; or from 0 to 2; or are 0 or 1. In other embodiments, m and n are each integers of from 0 to 3, wherein the sum of m+n is an integer of from 0 to 3; or m and n are each integers of from 0 to 2, wherein the sum of m+n is an integer of from 0 to 2; or m and n are each either 1 or 2 and the the sum of m+n is 1 or 2 (e.g., m=1 and n=1). In still other embodiments, o and p are each integers of from 0 to 3, wherein the sum of o+p is an integer of from 0 to 3; or o and p are each integers of from 0 to 2, wherein the sum of o+p is an integer of from 0 to 2; or o and p are each either 1 or 2, and the sum of o+p is either 1 or2(e.g., o=1 and p=1).
q1 is an integer from 0 to 5; or from 0 to 4; or from 0 to 3; or from 0 to 2; or is 0 or 1. In one embodiment, q1 is 2. In one aspect of the embodiment of q1=2, the substituted phenyl is either 2,4- or 3,4-di-substituted (e.g., 3,4-difluorophenyl).
t is an integer from 2 to 5; or from 2 to 4; or is 2 or 3; or is 2; or is 3.
u and v are each independently integers from 0 to 3; provided that u and v are not both zero; and further provided that when u is zero, Z is selected from CH2, CHF, CHRb, C(Rb)2, CF2, CHCHF2 and Cxe2x95x90CF2.
w is an integer from 0 to 3, provided that when w is 0, R20 is hydrogen. In other embodiments w is an integer from 0 to 2; or is 0 or 1; or is 0; or is 1.
Representative compounds of the present invention exhibit selectivity for the human alpha 1a adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
Representative-compounds of this invention display submicromolar affinity for the human alpha 1a adrenergic receptor subtype while displaying lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least about 10 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). Still other compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least about 20 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, in addition to exhibiting selectivity over other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
These compounds are administered in dosages effective to antagonize the alpha 1a receptor where such treatment is needed; e.g., treatment of BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of the compounds according to the invention or in the prepartion of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, n-methylglucamine ammonium salt, oleate, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, tosylate and valerate.
Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in combination with more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR(copyright) (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha 1a adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha 1a receptor mediated central nervous system events.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The term xe2x80x9cselective alpha 1a adrenergic receptor antagonist,xe2x80x9d as used herein, refers to an alpha 1a antagonist compound which is at least about ten fold selective for the human alpha 1a adrenergic receptor as compared to the human alpha 1b, alpha 1d, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
The term xe2x80x9clower urinary tract tissue,xe2x80x9d as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
The term xe2x80x9csubject,xe2x80x9d as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
The present invention includes pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt o f the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
As used herein, the term xe2x80x9ccompositionxe2x80x9d encompasses a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
The specificity of binding of compounds showing affinity for the alpha 1a receptor is shown by comparing affinity to membranes obtained from transfected cell lines that express the alpha 1a receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha 1d, alpha 1b) or beta adrenergic receptors. Expression of the cloned human alpha 1d, alpha 1b, and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha 1a adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
The ability of compounds of the present invention to specifically bind to the alpha 1a receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha 1a receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the 1a subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published Apr. 14, 1994 and WO 94/21660, published Sep. 29, 1994. The cloned human alpha 1a receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha 1d, alpha 1b, and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
Compounds of this invention exhibiting human alpha 1a adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. [See e.g., PCT International Application Publication No. WO94/10989, published May 26, 1994; U.S. Pat. No. 5,403,847, issued Apr. 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha 2 adrenergic receptors, the 3-adrenergic receptors, the muscarinic receptors, the serotonin receptors, the histamine receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alphal adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha 1a adrenergic receptor antagonists.
The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha 1a adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha 1a antagonistic agent.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug""s availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha 1a adrenergic receptor is required.
The daily dosage of the products may be varied over a wide range; e.g., from about 0.01 to about 1000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.001 to about 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to about 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha 1a adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this invention is administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR(copyright), (also known as finasteride, a 4-Aza-steroid; see U.S. Pat. Nos. 4,377,584 and 4,760,071, for example). In addition to PROSCAR(copyright), which is principally active in prostatic tissue due to its selectivity for human 5-a reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5a-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038; WO93/23048; WO93/23041;WO93/23040; WO93/23039; WO93/23376; WO93/23419, EP 0572165; WO93/23051.
The dosages of the alpha 1a adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha 1a adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly.
Thus, in one embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is from about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha 1a antagonist. In one aspect, the dosage of finasteride in the combination is from about 0.2 mg per subject per day to about 10 mg per subject per day, and, in another aspect, from about 1 to about 7 mg per subject to day (e.g., about 5 mg per subject per day).
For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha 1a adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a-reductase 1 inhibitor, such as 4,7xcex2-dimethyl-4-aza-5a-cholestan-3-one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha 1a adrenergic receptor antagonist and the 5a-reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Pat. No. 4,377,584 and U.S. Pat. No. 4,760,071 which describe dosages and formulations for 5a-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
DIPEA=diisopropyl ethylamine
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
EDTA=ethylenediamine tetraacetic acid
Et=ethyl
Et2O=diethyl ether
EtOAc=ethyl acetate
FAB MS=fast atom bombardment mass spectroscopy
LDA=lithium diisopropyl amide
LHMDS=lithium bis(trimethylsilyl)amide
Me=methyl
MeOH=methanol
NMR=nuclear magnetic resonance
PCTLC=preparative centrifugal thin layer chromatography
PMBCl=p-methoxybenzyl chloride
(p-NO2Ph)COCl=p-nitrophenylchloroformate
TFA=trifluoroacetic acid
THF=tetrahydrofuran
The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
Many of the compounds of the present invention can be prepared via Scheme 1 shown below. In Scheme 1, the ortho-aminoaryl- or o-aminoheteroaryl-nitrile 1 is treated with an arylmagnesium bromide or an aryllithium, followed by diethylcarbonate to afford aryl-substituted polyazanaphthalenone 2 (e.g., 4-aryl-quinazolin-2-one or 4-aryl-pteridin-2-one). Compound 2 is then reacted either with LHMDS and 4-methoxybenzyl chloride or with LHMDS and RAD (wherein R{circumflex over ( )} is C1-C8 alkyl or fluorinated C1-C8 alkyl, and D is chloro, bromo, iodo, mesylate, tosylate, nosylate, or triflate) to form nitrogen-alkylated analog 3. Compound 3 is reacted either with R1 Cu (other than R1=H) or with NaBH4 (to give R1=H) to form dihydro derivative 4. Deprotonation of 4 with a strong base (for example, LDA) and addition to a THF solution of p-nitrophenylchloroformate produces stable, isolable xe2x80x9cactivatedxe2x80x9d dihydro polyazanaphthalenone 5, which is coupled with amines of formula Qxe2x80x94H to give coupled product 6, which for R*=R{circumflex over ( )} (=R2 other than H) is a compound of the invention 7a. For R*=PMB, coupled product 6 is deprotected to afford 7b (i.e., R2=H).
Methods for preparing the amines of formula Qxe2x80x94H are described in U.S. Pat. No. 5,661,163, WO 98/57632, WO 98/57638, WO 98/57639, WO 98/57640, WO 98/57641 and WO 98/57642.
Scheme 2 illustrates the preparative procedures employed in Examples 1-6 below. 